Despite obvious clinical need, few new antibiotics have entered clinical practice in recent years. For ‘difficult to treat’ Gram-negative bacteria such as Pseudomonas aeruginosa, where the presence of an outer membrane and multi-drug efflux pumps severely limits the effectiveness of whole classes of antibiotics, the need is particularly pressing. In addition, the ability of P. aeruginosa to form multi-drug resistant biofilms during chronic infection can render this pathogen essentially untreatable with existing antibiotics. This is exemplified in cystic fibrosis patients where, despite aggressive antibiotic therapy, chronic lung infection with P. aeruginosa and the concomitant intense inflammatory response, leads to a progressive loss of lung function and is the major cause of mortality in this patient group.
An alternative strategy for antibiotic discovery is to utilize pyocins. These are narrow-spectrum protein antibiotics used by P. aeruginosa for intraspecies competition. We have shown that pyocins are highly active against a range of drug-resistant P. aeruginosa clinical isolates. Importantly, this potency is also apparent against phenotypically diverse strains growing in the biofilm state where cell survival of pyocin treated biofilms is several orders of magnitude lower than those treated with the front-line anti-pseudomonal agents tobramycin and aztreonam.
To determine if pyocins are also active during infection we have tested their ability provide protection against P. aeruginosa infection in the non-vertebrate host, Galleria mellonella. In this infection model, pyocins are highly effective against a range of clinical isolates and are also active against highly drug resistant small colony variants that commonly evolve during antibiotic therapy in cystic fibrosis patients. We are currently assessing the efficacy of pyocins in a mouse model of P. aeruginosa lung infection. Our preliminary data indicate strong efficacy in this model as measured by the reduction in colony forming units and importantly for a protein therapeutic; there is no evidence of inflammation or damage in lung tissue of uninfected pyocin treated mice.